Anti-arthritis effects of (E)-2,4-bis(p-hydroxyphenyl)- 2-butenal are mediated by inhibition of the STAT3 pathway

Background and Purpose

Products of Maillard reactions between aminoacids and reducing sugars are known to have anti-inflammatory properties. Here we have assessed the anti-arthritis effects of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal and its possible mechanisms of action.

Experimental Approach

We used cultures of LPS-activated macrophages (RAW264.7 cells) and human synoviocytes from patients with rheumatoid arthritis for in vitro assays and the collagen-induced arthritis model in mice. NO generation, iNOS and COX2 expression, and NF-κB/IKK and STAT3 activities were measured in vitro and in joint tissues of arthritic mice, along with clinical scores and histopathological assessments. Binding of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal to STAT3 was evaluated by a pull-down assay and its binding site was predicted using molecular docking studies with Autodock VINA.

Key Results

(E)-2,4-bis(p-hydroxyphenyl)-2-butenal (2.5–10 μg·mL⁻¹) inhibited LPS-inducedNO generation, iNOS and COX2 expression, and NF-κB/IKK and STAT3 activities in macrophage and human synoviocytes. This compound also suppressedcollagen-induced arthritic responses in mice by inhibiting expression of iNOS and COX2, and NF-κB/IKK and STAT3 activities; it also reduced bone destruction and fibrosis in joint tissues. A pull-down assay showed that (E)-2,4-bis(p-hydroxyphenyl)-2-butenal interfered with binding of ATP to STAT3. Docking studies suggested that (E)-2,4-bis(p-hydroxyphenyl)-2-butenal bound to the DNA-binding interface of STAT3 possibly inhibiting ATP binding to STAT3 in an allosteric manner.

Conclusions and Implications

(E)-2,4-bis(p-hydroxyphenyl)-2-butenal exerted anti-inflammatory and anti-arthritic effects through inhibition of the NF-κB/STAT3 pathway by direct binding to STAT3. This compound could be a useful agent for the treatment of arthritic disease.     

Rapid characterization of metabolites in soybean using ultra high performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-Q-TOF-MS/MS) and screening for α-glucosidase inhibitory and antioxidant properties through different solvent systems

This work was the first to investigate on the simultaneous characterization of metabolite profiles in soybean using UPLC-ESI-Q-TOF-MS/MS. Twenty two compositions were observed within 14 min from the methanol extract and confirmed as twelve isoflavones of three types and ten soyasaponins (Ab, Af, I–III, αg, βg, βa, γg, and γa). Moreover, the patterns of two chemicals showed considerable differences in seven solvent systems by HPLC analysis and their optimal extraction was achieved by 70% methanol (isoflavone: 4102.69 μg/g; soyasaponin: ten peaks). The second abundant isoflavones were detected in 50% methanol (4054.39 μg/g), followed by 30% methanol, 100% methanol, 10% methanol, CH₂Cl₂, and acetone extracts with 3134.03, 2979.49, 1681.33, 366.19, and 119.00 μg/g, respectively. Soyasaponins exhibited similar tendencies as those of isoflavones. The highest total phenolic was found as 2.10 ± 0.05 mg GAE/g in 70% methanol with remarkable differences by comparing other extracts. Specifically, this extract showed potent α-glucosidase inhibitory (81%) and antioxidant capacities (DPPH: 93% and ABTS: 95%) at a concentration of 1.0 mg/mL. Our results may be contributed to enhancing the value to functional foods and evaluating the secondary metabolites concern to antioxidant properties using solvent system in soybean.     

Protection by a transdermal patch containing physostigmine and procyclidine of soman poisoning in dogs

The prophylactic efficacy of a combinational patch system containing physostigmine and procyclidine against soman intoxication was evaluated using dogs. Female beagle dogs (body weights 9-10 kg) were shaved on the abdominal side, attached with a matrix-type patch (7x7 cm) containing 1.5% of physostigmine plus 6% procyclidine for 2 days, and challenged with subcutaneous injection of serial doses (2-10 LD50) of soman. Separately, in combination with the patch attachment, atropine (2 mg/dog) plus 2-pralidoxime (600 mg/dog) or atropine plus 1-[([4-(aminocarbonyl)pyridinio]methoxy)methyl]-2-[(hydroxyimino)methyl]pyridinium (HI-6, 500 mg/dog) were injected intramuscularly 1 min after soman poisoning. The LD50 value of soman was determined to be 9.1 microg/kg, and high doses (> or = 1.4 LD50) of soman induced salivation, emesis, defecation and diarrhea, tremors and seizures, and recumbency of dogs, leading to 100% mortality in 24 h. The prophylactic patch, which led to mean 18.5-18.8% inhibition of blood cholinesterase activity by physostigmine and mean 7.9-8.3 ng/ml of blood concentration of procyclidine, exerted a high protection ratio (4.7 LD50), in comparison with relatively-low effects of traditional antidotes, atropine plus 2-pralidoxime (2.5 LD50) and atropine plus HI-6 (2.7 LD50). Noteworthy, a synergistic increase in the protection ratio was achieved by the combination of the patch with atropine plus HI-6 (9 LD50), but not with atropine plus 2-pralidoxime (5 LD50). In addition, the patch system markedly attenuated the cholinergic signs and seizures induced by soman, especially when combined with atropine plus HI-6, leading to elimination of brain injuries and physical incapacitation up to 6 LD50 of soman poisoning. Taken together, it is suggested that the patch system containing physostigmine and procyclidine, especially in combination with atropine and HI-6, could be a choice for the quality survival from nerve-agent poisoning.     

The efficacy and safety of quetiapine for treatment of geriatric psychosis

Quetiapine, an atypical antipsychotic, is effective for psychosis in younger patients, with limited adverse effects reported. This open-label naturalistic study was conducted to assess the 4-week efficacy and safety of quetiapine for treatment of geriatric psychosis. Clinical efficacy was evaluated using the Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression Improvement (CGI-I) instruments before and after 4 weeks of quetiapine treatment. The sample population consisted of 100 geropsychiatric inpatients with psychosis, with the therapeutic evaluation completed by 91. Eighty-one of these 91 patients (89.0%) experienced mild-to-substantial improvement, as determined from the CGI-I. Further, a mean reduction in BPRS score of 39.5% (from baseline) was also determined. The mean daily dose of quetiapine for the fourth week was 276.1 177.2mg/day (range 50-800). Higher quetiapine dosages were administered for patients with functional psychoses compared to an analogous group with organic mental disorders. The most common adverse effects were somnolence (30.0%), lower-limb weakness (28.0%) and dizziness (27.0%). Body weight and fasting triglyceride were significantly elevated after quetiapine treatment (2.2% and 8.9% from baseline, respectively). Based on the results of this study, it appears that quetiapine is an efficacious and safe treatment for geriatric inpatients with psychosis, however, there is a wide dosing range and optimal dosage is diagnosis-dependent.     

Preparation and characterization of solid dispersions of itraconazole by using aerosol solvent extraction system for improvement in drug solubility and bioavailability

The objective of this study was to elucidate the feasibility to improve the solubility and bioavailability of poorly water-soluble itraconazole via solid dispersions by using supercritical fluid (SCF). Solid dispersions of itraconazole with hydrophilic polymer, HPMC 2910, were prepared by the aerosol solvent extraction system (ASES) under different process conditions of temperature/pressure. The particle size of solid dispersions ranged from 100 to 500 nm. The equilibrium solubility increased with decrease (15 to 10 MPa) in pressure and increase (40 to 60 degrees C) in temperature. The solid dispersions prepared at 45 degrees C/15 MPa showed a slight increase in equilibrium solubility (approximately 27-fold increase) when compared to pure itraconazole, while those prepared at 60 degrees C/10 MPa showed approximately 610-fold increase and no endothermic peaks corresponding to pure itraconazole were observed, indicating that itraconazole might be molecularly dispersed in HPMC 2910 in the amorphous form. The amorphous state of itraconazole was confirmed by DSC/XRD data. The pharmacokinetic parameters of the ASES-processed solid dispersions, such as Tmax, Cmax, and AUC(o-24 h) were almost similar to Sporanox capsule which shows high bioavailability. Hence, it was concluded that the ASES process could be a promising technique to reduce particle size and/or prepare amorphous solid dispersion of drugs in order to improve the solubility and bioavailability of poorly water-soluble drugs.     

Immune response to hepatitis B vaccination in drug using populations: A systematic review and meta-regression analysis

Injecting and non-injecting drug users are at increased risk of contracting HBV infection, and show lower antibody response to hepatitis B vaccination compared to the general population. This systematic review and meta-regression analysis aimed to estimate seroprotection rates and identify host or vaccine factors associated with varying immune response following hepatitis B vaccination in drug using populations. Original research articles were searched using online databases (Medline, PubMed, and Embase) and from reference lists of eligible articles. HBV vaccine intervention studies reporting seroprotection rates in drug users, published in English during or after 1989 were eligible. Of 978 citations reviewed, 11 studies were eligible and included for final analysis. The reported seroprotection rates ranged from 54.5% to 97.1%. The studies were significantly heterogeneous (Q = 180.850, p = 0.000). Measurement of anti-HBs antibody at 2 months after the third vaccine dose (RR = 2.62, 95%CI = 1.16–5.94, p = 0.026) was significantly associated with higher seroprotection rates compared to measurement at 1 month and 6 month following third vaccine dose. Age, gender, current drug use, vaccine dose and schedule, anti-HBc, anti-HCV and anti-HIV antibody seropositivity, and proportion of IDU study population did not show a significant association with seroprotection rates. Recommendations for future research include the definition of a standardized time point for the measurement of anti-HBs antibody levels, to enhance comparability of the immune response between different studies. Studies should strive to accurately report all potentially relevant factors affecting immune response to vaccine. Long-term follow up studies are needed to assess the seroprotection status in drug using populations receiving hepatitis B vaccine by standard or accelerated schedules.     

Influenza M2 virus-like particles confer a broader range of cross protection to the strain-specific pre-existing immunity

Immunity in humans with annual vaccination does not provide effective protection against antigenically distinct strains. As an approach to improve cross-protection in the presence of pre-existing strain-specific immunity, we investigated the efficacy of heterologous and heterosubtypic protection in previously vaccinated mice at earlier times after subsequent immunization with conserved-antigenic target influenza M2 ectodomain (M2e) virus-like particle vaccine (M2e5× VLP). Immunization of mice with H1N1 split vaccine induced virus specific antibodies to homologous influenza virus but did not provide heterosubtypic hemagglutination inhibiting antibody responses and cross-protection. However, subsequent M2e5× VLP immunization induced an M2e specific antibody response as well as interferon-γ (IFN-γ) producing cells in systemic and mucosal sites. Upon lethal challenge with H3N2 or H5N1 subtype influenza viruses, subsequently immunized mice with M2e5× VLP were well protected against heterosubtypic influenza viruses. These results provide evidence that non-seasonal immunization with M2e5× VLP, an experimental candidate for universal vaccine, is a promising approach for broadening the cross-protection even in the presence of strain-specific immunity.     

Curcumin attenuates adhesion molecules and matrix metalloproteinase expression in hypercholesterolemic rabbits

Curcumin, the yellow substance found in turmeric, possesses antioxidant, anti-inflammation, anticancer, and lipid-lowering properties. Because we hypothesized that curcumin could ameliorate the development of atherosclerosis, the present study focused on the effects and potential mechanisms of curcumin consumption on high-cholesterol diet–induced atherosclerosis in rabbits. During our study, New Zealand white rabbits were fed 1 of 3 experimental diets: a normal diet, a normal diet enriched with 1% cholesterol (HCD), or an HCD supplemented with 0.2% curcumin. At the end of 8 weeks, blood samples were collected to determine the levels of serum lipids, cytokines, and soluble adhesion molecule levels. Gene expression of adhesion molecules and matrix metalloproteinases (MMPs) in aortas were measured by quantitative real-time polymerase chain reaction and Western blot. Compared with the HCD group, rabbits fed an HCD supplemented with 0.2% curcumin had significantly less aortic lesion areas and neointima thickening. Curcumin reduced the levels of total cholesterol, triglyceride, low-density lipoprotein cholesterol, and oxidized low-density lipoprotein cholesterol in serum by 30.7%, 41.3%, 30.4%, and 66.9% (all P < .05), respectively, but did not affect high-density lipoprotein cholesterol levels. In addition, curcumin attenuated HCD-induced CD36 expression, circulating inflammatory cytokines, and soluble adhesive molecule levels. Curcumin reduced the mRNA and protein expression of intracellular adhesion molecule-1, vascular cell adhesion molecule-1, P-selectin, and monocyte chemotactic protein-1, and it inhibited HCD-induced up-regulation of MMP-1, MMP-2, and MMP-9. Our results demonstrate that curcumin exerts an antiatherosclerotic effect, which is mediated by multiple mechanisms that include lowering serum lipids and oxidized low-density lipoprotein, thus modulating the proinflammatory cytokine levels and altering adhesion molecules and MMP gene expression.     

Long-Term Psychological Outcome of Workers After Occupational Injury: Prevalence and Risk Factors

Introduction This study aimed to examine the prevalence rates of both post-traumatic stress disorder (PTSD) and major depression at 12 months in workers experiencing different types of occupational injury in Taiwan. Demographic and injury-related risk factors for psychological symptoms were also evaluated. Methods Our study candidates were injured workers in Taiwan who were hospitalized for 3 days or longer and received hospitalization benefits from the Labor Insurance program. A two-staged survey study was conducted. A self-reported questionnaire including the Brief Symptom Rating Scale and Post-traumatic Symptom Checklist was sent to workers at 12 months after injury. Those who met the criteria were recruited for the second-stage phone interview with a psychiatrist using the Mini-international Neuropsychiatric Interview (MINI). Results A total of 1,233 workers completed the questionnaire (response rate 28.0 %). Among them, 167 (13.5 %) fulfilled the criteria for the MINI interview and were invited. A total of 106 (63.5 %) completed the phone interview. The estimated rate of either PTSD/PPTSD or major depression was 5.2 %. The risk factors for psychological symptoms were female gender, lower education level, loss of consciousness after occupational injury, injury affecting physical appearance, occupational injury experience before this event, life experience before and after this injury, length of hospital stay, self-rated injury severity, and percentage of income to the family. Conclusions These results showed that occupational injury can cause long-term psychological impact in workers. Key demographic and injury characteristics may enhance the identification of at-risk occupational injured workers who would benefit from targeted screening and early intervention efforts.     

The Role of Leptin in the Association between Obesity and Psoriasis

Adipose tissue secretes many adipokines which contribute to various metabolic processes, such as blood pressure, glucose homeostasis, inflammation and angiogenesis. The biology of adipose tissue in an obese individual is abnormally altered in a manner that increases the body’s vulnerability to immune diseases, such as psoriasis. Psoriasis is considered a chronic inflammatory skin disease which is closely associated with being overweight and obese. Additionally, secretion of leptin, a type of adipokine, increases dependently on adipose cell size and adipose accumulation. Likewise, high leptin levels also aggravate obesity via development of leptin resistance, suggesting that leptin and obesity are closely related. Leptin induction in psoriatic patients is mainly driven by the interleukin (IL)-23/helper T (Th) 17 axis pathway. Furthermore, leptin can have an effect on various types of immune cells such as T cells and dendritic cells. Here, we discuss the relationship between obesity and leptin expression as well as the linkage between effect of leptin on immune cells and psoriasis progression.